Lnc-CCNH-8 promotes immune escape by up-regulating PD-L1 in hepatocellular carcinoma

Bixing Zhao; Xiaoyuan Zheng; Yang Wang; Niangmei Cheng; Yue Zhong; Yang Zhou; Jingyun Huang; Fei Wang; Xin Qi; Qiuyu Zhuang; Yingchao Wang; Xiaolong Liu

doi:10.1016/j.omtn.2024.102125

Lnc-CCNH-8 promotes immune escape by up-regulating PD-L1 in hepatocellular carcinoma

Mol Ther Nucleic Acids. 2024 Jan 23;35(1):102125. doi: 10.1016/j.omtn.2024.102125. eCollection 2024 Mar 12.

Authors

Bixing Zhao^{1

2

3}, Xiaoyuan Zheng^{1

2

3}, Yang Wang^{1

2}, Niangmei Cheng^{1

2

3}, Yue Zhong¹, Yang Zhou^{1

2

3}, Jingyun Huang^{1

2}, Fei Wang^{1

2

3}, Xin Qi^{1

2}, Qiuyu Zhuang^{1

2

3}, Yingchao Wang^{1

2

3}, Xiaolong Liu^{1

2

3}

Affiliations

¹ The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P.R. China.
² Mengchao Med-X Center, Fuzhou University, Fuzhou 350116, P.R. China.
³ Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors, Fuzhou 350025, P.R. China.

Abstract

Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis. In recent years, immune checkpoint inhibitors (ICIs) have enabled breakthroughs in the clinical treatment of patients with HCC, but the overall response rate to ICIs in HCC patients is still low, and no validated biomarker is available to guide clinical decision making. Here, we demonstrated that the long non-coding RNA Lnc-CCNH-8 is highly expressed in HCC and correlates with poor prognosis. Functionally, elevated Lnc-CCNH-8 inactivated co-cultured T cells in vitro and compromised antitumor immunity in an immunocompetent mouse model. Mechanistically, up-regulated Lnc-CCNH-8 can sponge microRNA (miR)-217 to regulate the expression of PD-L1. In addition, Lnc-CCNH-8 can also stabilize PD-L1 through miR-3173/PKP3 axis. Furthermore, mice bearing tumors with high Lnc-CCNH-8 expression had significant therapeutic sensitivity to anti-PD-L1 monoclonal antibody treatment. More important, HCC patients with high levels of plasma exosomal Lnc-CCNH-8 had a better therapeutic response to ICIs. Taken together, our results reveal the function of Lnc-CCNH-8 in inducing immune escape from CD8⁺ T-cell-mediated killing by up-regulating PD-L1 in a miR-217/miR-3173-dependent manner, which also reveals a novel mechanism of PD-L1 regulation in HCC, and exosomal Lnc-CCNH-8 can serve as a predictive marker for immunotherapy response in HCC.

Keywords: Lnc-CCNH-8; MT: Non-coding RNAs; PD-L1; hepatocellular carcinoma; immune escape; immunotherapy.